Tada, Masao (Sendai, JA)

05/527143

07/27/1976

11/25/1974

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Mitsui Pharmaceuticals, Incorporated (Tokyo, JA)

544/310

544/313

A61K31/505; C07D239/54; C07D239/553; C07D239/00; C07D239/54

260/260, 260/256.5R

Coughlan Jr., Paul M.

Fisher, Christen & Sabol

What is claimed is:

1. A 5-fluorouracil derivative represented by the formula ##SPC5##

wherein R₁ represents phenyl, halogen substituted phenyl, nitro substituted phenyl, methylphenyl, methoxyphenyl or 2-furyl.

2. The 5-fluorouracil derivative according to claim 1 wherein R₁ is p-chlorophenyl and the compound is 1-(p-chlorobenzoyl)-5-fluorouracil.

3. The 5-fluorouracil derivative according to claim 1 wherein R₁ is p-methoxyphenyl and the compound is 5-fluoro-1-(p-methoxybenzoyl)uracil.

4. The 5-fluorouracil derivative according to claim 1 wherein R₁ is p-nitrophenyl and the compound is 5-fluoro-1-(p-nitrobenzoyl)uracil.

5. The 5-fluorouracil derivative according to claim 1 wherein R₁ is phenyl and the compound is 1-benzoyl-5-fluorouracil.

6. The 5-fluorouracil derivative according to claim 1 wherein R₁ is p-methylphenyl and the compound is 5-fluoro-1-(p-methylbenzoyl)uracil.

7. The 5-fluorouracil derivative according to claim 1 wherein R₁ is o-methoxyphenyl and the compound is 5-fluoro-1-(o-methoxybenzoyl)uracil.

8. The 5-fluorouracil derivative according to claim 1 wherein R₁ is 2,4-dichlorophenyl and the compound is 1-(2,4-dichlorobenzoyl)-5-fluorouracil.

9. The 5-fluorouracil derivative according to claim 1 wherein R₁ is o-methylphenyl and the compound is 5-fluoro-1-(o-methylbenzoyl)uracil.

10. The 5-fluorouracil derivative according to claim 1 wherein R₁ is 2-furyl and the compound is 5-fluoro-1-(2-furoyl)uracil.

11. A 5-fluorouracil derivative represented by the formula ##SPC6##

wherein R₂ represents methyl, ethyl, phenyl, methyl or ethyl substituted phenyl, halogen substituted phenyl, nitro substituted phenyl, acetamido substituted phenyl, naphthyl, thiofuryl, quinolyl or camphoryl.

12. The 5-l -fluorouracil derivative according to claim 11 wherein R₂ is methyl and the compound is 5-fluoro-1-methanesulfonyluracil.

13. The 5-fluorouracil derivative according to claim 11 wherein R₂ is phenyl and the compound is 1-benzenesulfonyl-5-fluorouracil.

14. The 5-fluorouracil derivative according to claim 11 wherein R₂ is p-tolyl and the compound is 5-fluoro-1-(p-toluenesulfonyl)uracil.

15. The 5-fluorouracil derivative according to claim 11 wherein R₂ is o-methylphenyl and the compound is 5-fluoro-1-(o-methylbenzenesulfonyl)uracil.

16. The 5-fluorouracil derivative according to claim 11 wherein R₁ is ethyl and the compound is 1-ethylsulfonyl-5-fluorouracil.

17. The 5-fluorouracil derivative according to claim 11 wherein R₂ is p-chlorophenyl and the compound is 1-(p-chlorobenzenesulfonyl)-5-fluorouracil.

18. The 5-fluorouracil derivative according to claim 11 wherein R₂ is p-iodophenyl and the compound is 5-fluoro-1-(p-iodobenzenesulfonyl)uracil.

19. The 5-fluorouracil derivative according to claim 11 wherein R₂ is p-ethylphenyl and the compound is 1-(p-ethylbenzenesulfonyl)-5-fluorouracil.

20. The 5-fluorouracil derivative according to claim 11 wherein R₂ is p-acetamidophenyl and the compound is 1-(p-acetamidobenzenesulfonyl)-5-fluorouracil.

21. The 5-fluorouracil derivative according to claim 11 wherein R₂ is 2,4,6-trimethylphenyl and the compound is 5-fluoro-1-(2,4,6-trimethylbenzenesulfonyl)uracil.

22. The 5-fluorouracil derivative according to claim 11 wherein R₂ is o-nitrophenyl and the compound is 5-fluoro-1-(o-nitrobenzenesulfonyl)uracil.

23. The 5-fluorouracil derivative according to claim 11 wherein R₂ is β-naphthyl and the compound is 5-fluoro-1-(naphthalene-β-sulfonyl)uracil.

24. The 5-fluorouracil derivative according to claim 11 wherein R₂ is p-bromophenyl and the compound is 1-(p-bromobenzenesulfonyl)-5-fluorouracil.

25. The 5-fluorouracil derivative according to claim 11 wherein R₂ is 2-thiofuryl and the compound is 5-fluoro-1-(2-thiophenesulfonyl)uracil.

26. The 5-fluorouracil derivative according to claim 11 wherein R₂ is 8-quinolyl and the compound is 5-fluoro-1-(8-quinolinesulfonyl)uracil.

27. The 5-fluorouracil derivative according to claim 11 wherein R₂ is camphoryl and the compound is 1-(d-camphorsulfonyl)-5-fluorouracil.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to 5-fluorouracil derivatives and, more particularly, to novel 5-fluorouracil derivatives represented by the formula ##SPC2##

Wherein R represents arylcarbonyl, substituted arylcarbonyl, heterocyclic carbonyl, alkylsulfonyl, arylsulfonyl, substituted arylsulfonyl, heterocyclic sulfonyl or alicyclic sulfonyl.

DESCRIPTION OF THE PRIOR ART

5-Fluorouracil is well known to be an effective antimetabolite used as an agent for mammary gland or gastrointestinal cancer therapy. However, because of its high toxicity, 5-fluorouracil is not considered to be a favorable anti-cancer agent and improvement has been recognized as necessary. On the other hand, as a low toxic 5-fluorouracil derivative, there is known 5-fluoro-1-(2-tetrahydrofuryl)uracil which has been used as an anti-tumor agent. However, this compound is substantially inferior to 5-fluorouracil in anti-tumor activity and it has been desired to develop 5-fluorouracil derivatives which are as non-toxic as 5-fluoro-1-(2-tetrahydrofuryl)uracil and are also substantially more effective anti-metabolites.

SUMMARY OF THE INVENTION

The 5-fluorouracil derivatives of the present invention are more effective anti-metabolites than 5-fluoro-1-(2-tetrahydrofuryl)uracil and are as low in toxicity as that prior art compound. The 5-fluorouracil derivatives of the present invention may be prepared in various ways.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The 5-fluorouracil derivatives of the formula ##SPC3##

Wherein R ₁ represents aryl containing from 6 to 10 carbon atoms, halogen substituted aryl, alkyl and alkoxy substituted aryl wherein the alkyl or alkoxy group contains from 1 to 6 carbon atoms, nitro substituted aryl or a heterocyclic group are prepared by acylating 5-fluorouracil with acyl halides of the formula R ₁ --COX

wherein R ₁ represents the same groups described above and X represents halogen.

Similarly the 5-fluorouracil derivatives of the formula ##SPC4## wherein R ₂ represents alkyl containing from 1 to 6 carbon atoms, aryl containing from 6 to 10 carbon atoms, alkyl substituted aryl wherein the alkyl group contains from 1 to 6 carbon atoms, halogen substituted aryl, nitro substituted aryl, amido substituted aryl, a heterocyclic group or an alicyclic group are prepared by condensing 5-fluorouracil with sulfonyl halides of the formula R ₂ --SO ₂ X

wherein R ₂ represents the same groups described above and X represents halogen.

The above-described acylation or condensation of 5-fluorouracil is ordinarily carried out in an organic solvent. Organic solvents such as dioxane, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, acetonitrile, and the like are suitable for this purpose. 5-Fluorouracil is dissolved or suspended in the organic solvent, one of the above-described halides is added thereto and the reaction mixture is stirred at a temperature ranging from room temperature to the reflux temperatures of the reaction mixture. The reaction is preferably carried out in the presence of an acid acceptor of the halogen halide formed during the reaction. Such acid acceptors include, for example, triethylamine, pyridine, potassium carbonate, sodium bicarbonate, sodium hydride, and the like. The reaction mixture is preferably concentrated under reduced pressure, the residue is dissolved again in an organic solvent and, after cooling, the resultant crystals are filtered off.

The 5-fluorouracil derivatives thus obtained are white needles, leaflets or granules and are excellent as anti-cancer agents.

The following Examples illustrate methods of preparing the 5-fluorouracil derivatives of the present invention.

EXAMPLE 1

2.6 g (0.02 mole) of 5-fluorouracil was suspended in a mixed solution of 40 ml. of dioxane and 10 ml. of triethylamine. 8.4 g (0.04 mole) of p-chlorobenzoyl chloride was added to the suspension and stirred at 80°C. for 6 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated to dryness under reduced pressure and 2.7 g of residue was obtained. The residue was extracted with absolute alcohol and the extract was concentrated by evaporation. After cooling to room temperature, the resulting crystals were filtered and dried to give 1-(p-chlorobenzoyl)-5-fluorouracil weighing 1.18 g (35.1% yield). Recrystallization thereof from ethanol gave needles melting at 185°-186° C. Results of an elementary analysis were well in agreement with the calculated value as follows: C H Cl F N Found (%) 49.38 2.54 13.13 7.10 10.29 Calcl. (%) 49.18 2.25 13.22 7.08 10.43 (for C ₁₁ H ₆ ClFN ₂ O ₃ )

EXAMPLE 2

1.3 g (0.01 mole) of 5-fluorouracil was suspended in a mixed solution of 40 ml. of dioxane and 2 ml. of pyridine. 1.7 g (0.01 mole) of p-methoxybenzoyl chloride in 5 ml. of dioxane was added to the suspension and stirred at 80°C. for 5 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and a resinous residue was obtained. The residue was dissolved in ethanol and filtered. After cooling to 0°C., the resulting crystals were filtered and dried to give 1.30 g (49.2% yield) of 5-fluoro-1-(p-methoxybenzoyl)uracil. The product was recrystallized from dioxane-ethanol and white needles melting at 200°-201°C. were obtained. The results of an elementary analysis thereof were well in agreement with the calculated value as follows: C H F N Found (%) 54.56 3.62 7.18 10.35 Calcd. (%) 54.55 3.43 7.20 10.60 (for C ₁₂ H ₉ FN ₂ O ₄ )

EXAMPLE 3

2.6 g (0.02 mole) of 5-fluorouracil was reacted with 9.28 g (0.05 mole) of p-nitrobenzoyl chloride in the same manner as in Example 1 and 2.95 g (52.9% yield) of 5-fluoro-1-(p-nitrobenzoyl)uracil was obtained. The product was recrystallized from ethanol and white needles melting at 182°-183°C. were obtained. The results of an elementary analysis of the above crystals were well in agreement with the calculated value as follows: C H F N Found (%) 47.50 2.25 6.79 15.19 Calcd. (%) 47.32 2.17 6.81 15.05 (for C ₁₂ H ₉ FN ₃ O ₄ )

EXAMPLE 4

2.6 g (0.02 mole) of 5-fluorouracil was suspended in a mixed solution of 35 ml. of dioxane and 10 ml. of pyridine and reacted with 6.7 g (0.048 mole) of benzoylchloride. The reaction mixture was treated in the same manner as in Example 1 and 2.00 g (42.5% yield) of 1-benzoyl-5-fluorouracil was obtained. The product was recrystallized from ethanol to give white needles melting at 170°-172°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows: C H F N Found (%) 56.68 3.01 8.07 11.83 Calcd. (%) 56.42 3.01 8.12 11.96 (for C ₁₁ H ₇ FN ₂ O ₃ )

Other acylated 5-fluorouracil derivatives of the present invention prepared in a similar manner are summerized in Table 1 below.

TABLE 1

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Ex. Compound M.P. No. (°C)

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5 5-fluoro-1-(p-methylbenzoyl)uracil 198-199 6 5-fluoro-1-(o-methoxybenzoyl)uracil 183-184 7 1-(2,4-dichlorobenzoyl)-5-fluorouracil 175-177 8 5-fluoro-1-(o-methylbenzoyl)uracil 179-180 9 5-fluoro-1-(2-furoyl)uracil 166-167

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EXAMPLE 10

2.6 g. (0.02 mole) of 5-fluorouracil and 1.52 g (0.011 mole) of anhydrous potassium carbonate were suspended in 50 ml. of dioxane and then 2.53 g (0.022 mole) of methanesulfonyl chloride in 20 ml. of dioxane was dropwise added thereto. After stirring at 80°C. for 10 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and a resinous residue was obtained. The residue was dissolved in a small amount of methanol and allowed to stand at 0°C. overnight. There was obtained 1.48 g (45.4% yield) of 5-fluoro-1 -methanesulfonyluracil. Recrystallization of the product from methanol gave leaflets melting at 223°-224°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows: C H F N S Found (%) 28.64 2.42 9.15 13.28 15.37 Calcd. (%) 28.85 2.42 9.13 13.46 15.38 (for C ₅ H ₅ FN ₂ O ₄ S)

EXAMPLE 11

2.6 g (0.02 mole) of 5-fluorouracil and 1.38 g (0.01 mole) of anhydrous potassium carbonate were suspended in 70 ml. of dioxane. 3.5 g (0.02 mole) of benzenesulfonyl chloride in 10 ml. of dioxane was dropwise added thereto and stirred at 80°C. for 7 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and a resinous residue was obtained. The residue was dissolved in a small amount of ethanol and allowed to stand at 5°C. overnight. There was obtained 2.95 g (54.6% yield) of 1-benzenesulfonyl-5-fluorouracil. The product was recrystallized from dioxane-ethanol and gave granular crystals melting at 256°-257°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows: C H F N S Found (%) 44.58 2.53 7.13 10.06 11.81 Calcd. (%) 44.44 2.61 7.04 10.37 11.85 (for C ₁₀ H ₇ FN ₂ O ₄ S)

EXAMPLE 12

2.6 g (0.02 mole) of 5-fluorouracil and 1.28 g (0.01 mole) of anhydrous potassium carbonate were suspended in 50 ml. of dioxane and reacted with 3.82 g (0.02 mole) of p-toluenesulfonyl chloride in the same manner as in Example 10. There was obtained 3.54 g (62.3% yield) of 5-fluoro-1-(p-toluenesulfonyl)uracil. Recrystallization of the product from methanol-chloroform gave leaflets melting at 241°-242°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows: C H F N S Found (%) 46.47 3.31 6.64 9.55 11.25 Calcd. (%) 46.48 3.19 6.69 9.86 11.27 (for C ₁₁ H ₉ FN ₂ O ₄ S)

Other sulfonylated 5-fluorouracil derivatives of the present invention prepared in a similar manner are summerized in Table 2 below.

TABLE 2

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Ex. Compound M.P. No. (°C)

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13 5-fluoro-1-(o-methylbenzenesulfonyl)uracil 204-205 14 1-ethylsulfonyl-5-fluorouracil 214-215 15 1-(p-chlorobenzenesulfonyl)-5-fluorouracil 237-238 16 5-fluoro-1-(p-iodobenzenesulfonyl)uracil 253-254 17 1-(p-ethylbenzenesulfonyl)-5-fluorouracil 215-216 18 1-(p-acetamidobenzenesulfonyl)-5-fluorouracil 240-241 19 5-fluoro-1-(2,4,6-trimethylbenzenesulfonyl)uracil 232-233 20 5-fluoro-1-(o-nitrobenzenesulfonyl)uracil 229-231 21 5-fluoro-1-(naphthalene-β-sulfonyl)uracil 218-221 22 1-(p-bromobenzenesulfonyl)-5-fluorouracil 247-248 23 5-fluoro-1-(2-thiophenesulfonyl)uracil 222-223 24 5-fluoro-1-(8-quinolinesulfonyl)uracil 272-273 25 1-(d-camphorsulfonyl)-5-fluorouracil 153-160

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The anti-tumor activities of the 5-fluorouracil derivatives of the present invention were measured according to the procedure set forth below, and compared with that of well known 5-fluoro-1-(2-tetrahydrofuryl)uracil.

Procedure for the Measurement of Anti-tumor Activity

BDF ₁ mice weighing 18-20 g and caused to have lymphatic leukemia (L-1210) were used for this purpose. Each test compound and 5-fluoro-1-(2-tetrahydrofuryl)uracil as a standard was administered intraperitoneally to the mice at a daily dosage of 30 mg/Kg for 5 days and the percent Increased Life Span (ILS%) was observed.

The results of the above-described anti-tumor activity measurements made according to the above procedure are summarized in Table 3.

TABLE 3

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Compound ILS(%)

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5-fluoro-1-(2-tetrahydrofuryl)uracil 100 (Standard) 1-(p-chlorobenzoyl)-5-fluorouracil 151 5-fluoro-1-(p-methoxybenzoyl)uracil 145 5-fluoro-1-(p-nitrobenzoyl)uracil 136 1-benzoyl-5-fluorouracil 163 5-fluoro-1-(p-methylbenzoyl)uracil 137 5-fluoro-1-(o-methoxybenzoyl)uracil 135 1-(2,4-dichlorobenzoyl)-5-fluorouracil 133 5-fluoro-1-(o-methylbenzoyl)uracil 134 5-fluoro-1-(2-furoyl)uracil 125 5-fluoro-1-methanesulfonyluracil 96 1-benzenesulfonyl-5-fluorouracil 144 5-fluoro-1-(p-toluenesulfonyl)uracil 141 5-fluoro-1-(o-methylbenzenesulfonyl)uracil 102 1-ethylsulfonyl-5-fluorouracil 132 1-(p-chlorobenzenesulfonyl)-5-fluorouracil 138 5-fluoro-1-(p-iodobenzenesulfonyl)uracil 108 1-(p-ethylbenzenesulfonyl)-5-fluorouracil 129 1-(p-acetamidobenzenesulfonyl)-5-fluorouracil 104 5-fluoro-1-(2,4,6-trimethylbenzenesulfonyl) 148 uracil 5-fluoro-1-(o-nitrobenzenesulfonyl)uracil 138 5-fluoro-1-(naphthalene-β-sulfonyl)uracil 146 1-(p-bromobenzenesulfonyl)-5-fluorouracil 121 5-fluoro-1-(2-thiophenesulfonyl)uracil 102 5-fluoro-1-(8-quinolinesulfonyl)uracil 109 1-(d-camphorsulfonyl)-5-fluorouracil 106

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